Osteoclastic bone resorption requires physical intimacy between the bone degrading cell and the juxtaposed matrix. In this regard, we have focused on the role of integrins in osteoclast formation and function and find that the integrin avb3 is fundamental to the process. While, these studies have eventuated in the development of integrin inhibitory agents which retard experimental and human post-menopausal osteoporosis, optimizing avb3 as a therapeutic target will depend upon delineating the mechanisms by which it functions in the osteoclast. We proposed in our original application to identify specific components of the b3 integrin cytoplasmic domain which 1) regulate activation of intraosteoclastic signaling molecules 2) organize the osteoclast cytoskeleton and 3) regulate the capacity of osteoclasts to resorb bone. Using beta3-/- mice generated in our laboratory we have achieved each of these Specific Aims. In the current application, we continue to address the mechanisms by which alphavbeta3 transmits important intra-osteoclastic signals. Thus, we propose a model in which ligand occupancy of alphavbeta3 prompts formation of a ternary signaling complex consisting of the integrin, c-Src and Syk/Zap70. This avb3 associated complex, in turn, activates Vav3 and Rac, eventuating in organization of the OC cytoskeleton and bone resorption. Similar to our original application, we are positioned to achieve our goals as we have in hand gene deleted mice to address each issue, as well as the capacity to express proteins of interest in osteoclasts derived from such mice. We, therefore, hypothesize that 1) alphavbeta3 and c-Src interact in osteoclasts; 2) c-Src and Syk family kinases mediate alphavbeta3 activation of Vav3; 3) Rac, an effector of avb3, regulates osteoclast formation and/or function. Thus, our Specific Aims are to determine the mechanisms by which 1) c-Src and alphavbeta3 interact in osteoclasts; 2) Syk/Zap70 and alphavbeta3 activate Vav3 in osteoclasts; and 3) Rac, an effector of avb3 regulates osteoclast formation and/or function.